The overall aim of the proposed research is to determine the common developmental defect evoked by a series of recessive allelic genes at the T-locus in the mouse. In a series of studies we have found that the phenotypic expression of tn/tn genotypes, which are lethal to preimplantation staged mouse embryos, includes aberrant ATP synthetic rates, abnormal patterns of lipid metabolism and depressed cAMP content prior to death. The lethal phenotype can be suppressed and the lifespan of the homozygous mutant embryos extended by culturing them in a specific medium. Similarly, the lifespan of trophoblast cells from a tn/tn embryo which dies following uterine implantation can be extended by placing these mutants embryos, at the blastocyst stage, into a specific "outgrowth" medium. Our ultrastructural and biochemical studies of the "saved" preimplantation tn/tn embryos suggest that these embryos are normal in both their patterns of lipid biosynthesis and in their cAMP content. We propose to undertake additional comparative biochemical and ultrastructural studies on "saved" and dying tn/tn embryos and cells in order to elucidate the metabolic and structural differences between them. These comparisons will aid in delimiting the primary effect of the lethal tn/tn genotypes.